tbuckley/cabot-search huggingface dataset:
Long-term outcomes of a phase II trial of neoadjuvant immunotherapy for advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN).
Authors: Neil D. Gross, Renata Ferrarotto, Moran Amit, Priyadharsini Nagarajan, Ying Yuan, Diana Bell, Jason M. Johnson, William H. Morrison, David Ira Rosenthal, Bonnie S. Glisson, Faye M. Johnson, Frank Mott, Bita Esmaeli, Eduardo Diaz, Paul Gidley, Ryan Goepfert, Carol M. Lewis, Jennifer Ann Wargo, Randal S. Weber, Jeffrey Myers
Journal: Journal of Clinical Oncology (2022)

9519 Background: In a pilot phase II trial, we investigated the use of neoadjuvant immunotherapy to induce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Here, we report the long-term outcomes according to pathologic response. Methods: Patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, pathologic response, disease-free and overall survival. Results: Of 20 patients enrolled, 7 (35%) had recurrent disease and 12 (60%) were stage IV on presentation. Neoadjuvant immunotherapy was generally well-tolerated and there were no surgical delays. Adverse events (AEs) were observed in 7 (35%) patients; 1 (5%) grade 3 diarrhea, 6 (30%) ≤ grade 2 AEs. ORR by RECIST was 30%. However, 85% (17/20) achieved a pathologic response (≤50% viable tumor), with pathologic complete response (pCR) in 11 (55%), major pathologic response (MPR, ≤10% viable tumor) in 4 (20%) and pathologic partial response (pPR, &gt;10% and ≤50% viable tumor) in 2 (10%). Patients with a pCR did not receive planned radiotherapy after surgery. Patients who did not have a pathologic response (&gt; 50% viable tumor) either progressed and died (1, 5%) or developed recurrence (2, 10%) despite surgery and adjuvant radiation or chemoradiation. At a median follow up of 34.5 months (range: 7.7-42.7), none of the patients who achieved a pathologic response have recurred. Conclusions: Consistent with other cancer types, pathologic response to neoadjuvant immunotherapy is durable in patients with advanced, resectable CSCC-HN. Adjuvant radiation therapy may be spared in patients who achieve a pCR and warrants further investigation. Clinical trial information: NCT03565783.
Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner
Authors: Wei Wang, Luciane M. Silva, Henry H. Wang, Matthew A. Kavanaugh, Tana S. Pottorf, Bailey A. Allard, Damon T. Jacobs, Ruochen Dong, Joseph T. Cornelius, Aakriti Chaturvedi, Katherine I. Swenson-Fields, Timothy A. Fields, Michele T. Pritchard, Madhulika Sharma, Chad Slawson, Darren P. Wallace, James P. Calvet, Pamela V. Tran
Journal: Kidney International (2022)
HER2-targeted immunoconjugates for breast cancer: Ancestry and dose adjustment for thrombocytopenia.
Authors: Michael Rainone, Carolyn E. Behrendt, Saro Kasparian, Tina Nguyen, Joanne E. Mortimer, Yuan Yuan, James Ross Waisman, Daphne B. Stewart, Sayeh Moazami Lavasani, Mina S. Sedrak, Niki Patel, Vinod A. Pullarkat
Journal: Journal of Clinical Oncology (2022)

1048 Background: Thrombocytopenia (TCP) is a common toxicity of HER2-targeted agents, trastuzumab emtansine (TDM1) and trastuzumab deruxtecan (TDXd). A high incidence of this toxicity was observed in pivotal trials that led to approval of these agents. We investigated whether Asian ancestry increases risk of dose adjustment for TCP on TDM1/TDXd and its impact on dosing in the real-world setting. Methods: Females with HER2+ breast cancer who initiated TDM1/TDXd between 1/16/17-10/26/21 were identified by retrospective review. Primary endpoint was number of chemotherapy cycles until adjustment of TDM1/TDXd dose for TCP; competing endpoints included discontinuation for other toxicity, disease progression, and completion of treatment. Individuals who were switched from TDM1 to TDXd contributed an additional observation post-switch. Recurrent events analysis evaluated Asian ancestry (p&lt;0.05) using a proportional means model, with robust sandwich estimate recognizing correlation between repeated observations per individual. Covariates (age, metastatic disease, drug, prior adjustment) were retained if they improved the model. Results: The study excluded individuals who declined to self-identify (n=23), self-identified as other than Asian or White (n=28), and/or dissented to research (n=24). The study included n=181 individuals (mean age 55.1+12.8 years), of whom n=48 (26.5%) identified as Asian and n=124 (68.5%) had metastatic disease. Overall, 33 individuals received TDXd exclusively, leaving 148 (81.8%) individuals who received TDM1, including 45 individuals who later switched to TDXd after development of TCP while on TDM1 (n=9) or other toxicity (n=36) on TDM1. For n=226 observations (total 2551 cycles), the endpoint was dose adjustment for TCP (n=32), discontinuation for other toxicity or disease progression (n=112), completion of treatment (n=27), or censoring (n=55). Taking into account history of switching drug for TCP, Asian ancestry was associated with increased risk of dose adjustment for TCP (Table). Neither age, metastatic disease, nor specific drug improved the model (data not shown). Conclusions: Among individuals taking TDM1 and/or TDXd for HER2+ breast cancer, we observed that those with Asian ancestry are at greater risk of dose reduction for TCP than their non-Asian counterparts. Upon confirmation in additional individuals with HER2+ cancers of the breast and other sites, this heightened susceptibility to TCP among Asian individuals should be further investigated to elucidate the underlying mechanism and optimize clinical guidelines for prevention and management. [Table: see text]
Youth Characteristics Associated With Sexual Violence Perpetration Among Transgender Boys and Girls, Cisgender Boys and Girls, and Nonbinary Youth
Authors: Michele L. Ybarra, Kimberly L. Goodman, Elizabeth Saewyc, Jillian R. Scheer, Ida F. Stroem
Journal: JAMA Network Open (2022)

Gender minority adults experience higher rates of sexual violence (SV) than cisgender adults. How this disparity extends to youths, including perpetration rates, is unknown.
MODL-24. Focused ultrasound-mediated blood-brain barrier opening and panobinostat in a thalamic syngeneic murine DMG model is feasible and safe.
Authors: Andrea Webster Carrion, Hong-Jian Wei, Nicholas McQuillan, Masih Tazhibi, Danae Kokossis, Xander Berg, Hanna Minns, Xu Zhang, Zhiguo Zhang, Junqiang Wang, Ester Calvo Fernandez, Chia-Ing Jan, Oscar Padilla, Robyn D Gartrell, Oren Becher, James H Garvin Jr, Jovana Pavisic, Luca Szalontay, Elisa E Konofagou, Stergios Zacharoulis, Cheng-Chia Wu
Journal: Neuro-Oncology (2022)

Abstract Diffuse Midline Glioma with H3K27M mutation (DMG) is an aggressive unresectable central nervous system tumor of the brainstem, midline thalamus, or spine. Prognosis is poor and systemic agents have been ineffective partially due to limited permeability of the blood brain barrier (BBB). Non-invasive low intensity focused ultrasound (FUS) can be used for BBB opening (BBBO). Our preclinical studies showed safety and feasibility of targeting and BBBO in the brainstem; however, to our knowledge, FUS-guided BBBO for thalamic DMG has yet to be reported. RNA-seq was performed on mouse syngeneic DMG cells 4423 (PDGFB+, H3.3K27M, p53−/−) and results recapitulated molecular programs seen in human tumors. 4423 cells were injected into the thalamus of male B6 (Cg)-Tyrc-2J/J mice at 1.6mm lateral and 1.8mm posterior to the bregma at a depth of 3.2mm. MRI at 14-21 days post injection confirmed thalamic tumor growth. Histological analysis with Hematoxylin and Eosin stain was consistent with thalamic DMG. Tumor implantation rate was 85% and median survival was 38 days post injection. To test safety and feasibility of BBBO for thalamic tumors, a 1.5 MHz FUS transducer was used with concurrent microbubble injection. BBBO assessed by contrast-enhanced MRI. FUS achieved BBBO targeting the thalamic tumor without increased morbidity or mortality and BBB closure was observed on day 3 post-sonication. Next we tested the tolerance of drug delivery with panobinostat post-FUS at a dose of 20mg/kg weekly. The results are preliminary at this time; however, animals tolerated the combination therapy without morbidity or mortality. Preclinical models are crucial to improve the development of new therapeutic strategies. Establishing this syngeneic thalamic DMG murine model provides the opportunity to test FUS as a non-invasive drug delivery technology for thalamic DMG compared to brainstem DMG, and to re-visit therapeutic agents previously considered ineffective due to limited penetration of the BBB.
Preoperative anemia in gynecologic oncology surgery: Analysis of the National Surgical Quality Improvement Program Database.
Authors: Abigail Cain, Valerie Bianca Galvan-Turner
Journal: Journal of Clinical Oncology (2022)

e13528 Background: Preoperative anemia has been identified as risk factor for adverse postoperative outcomes following hysterectomy for benign indications. However, studies have not yet been performed looking at the effect of preoperative anemia on women undergoing surgery for a gynecologic malignancy. Methods: We used the National Surgical Quality Improvement Program data from 2014 to 2019 to conduct a retrospective, population-based cohort study. Our exposure of interest was preoperative anemia, defined as a hemoglobin value &lt;12 g/dL and stratified using the National Cancer Institute grading system. We preformed a logistic regression was used to calculate the adjusted odds ratio evaluate the effect of anemia on the outcomes. Results: Of the 54,569 women in the cohort, 13,232 (24.2%) had anemia. Conclusions: Preoperative anemia, at any grade, is associate with an increase in postoperative morbidity and that the effect is increased with worsening grade of anemia.[Table: see text]
Assessment of proarrhythmogenic risk for cannabidiol using dog and rabbit cardiac preparations: the electrophysiological effects on action potential and transmembrane potassium currents
Authors: M Naveed, L Topal, J Prorok, B Paszti, D Csupor, I Baczko, L Virag, N Jost, A Varro
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Economic Development and Innovation Operative Programme GINOP-2.3.2-15-2016-00012, the National Research Development and Innovation Office (NKFIH K 135464 and NKFIH K 128851), the Ministry of Human Capacities Hungary (20391-3/2018/FEKUSTRAT and EFOP-3.6.2-16-2017-00006), and from the Eötvös Loránd Research Network Background Cannabidiol (CBD), a major active phytogenic cannabinoid, is one of the main constituents of cannabis. Cannabis has been widely used as recreational drug over the decades and its use is constantly increasing as hallucinogenic and/or medicinal agent. However, significant cardiovascular side effects can accompany its use ranging from arrhythmia to sudden cardiac death. Purpose The aim of the present work was to investigate the possible cardiac adverse electrophysiological effects of cannabidiol (CBD) on action potentials and various transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations to assess the cardiac safety profile and proarrhythmic risk. Methods In the current study, conventional microelectrode and voltage clamp techniques were used to record the action potential and transmembrane ionic currents in dog and rabbit ventricular tissue preparations and enzymatically isolated myocytes, respectively. Results The results show that CBD lengthens APD90 significantly at the concentration of 5 µM both in dog and rabbit ventricular tissues without changing other action potential parameters significantly. To further investigate the APD90 lengthening effect of CBD, transmembrane potassium currents (IKr, IKs, Ito and IK1) were investigated in dog and/or rabbit ventricular myocytes using voltage clamp technique. CBD significantly inhibited IKr and IKs currents in rabbit ventricular myocytes with an estimated EC50 values of 4.9 and 3.1 µM, respectively. The effect of CBD on rabbit’s Ito current was not significant while it was significant on dog’s Ito current with an estimated EC50 value of 5 µM. IK1 was not responsive to CBD even at high concentration. Conclusion In conclusion, looking at the inhibitory effects of CBD on repolarizing potassium currents, despite of the fact that these calculated EC50 values are higher than pharmacokinetics based Cmax values of CBD recorded after smoking and oral intake, it can be speculated that in the presence of certain cardio active drugs or co-morbidity where CBD metabolism or cardiac repolarization reserve is impaired CBD can have an additive and proarrhythmic effect.
Efficacy of sacituzumab govitecan based regimen in triple-negative breast cancer: A systematic review.
Authors: Farhan Khalid, Richi Kashyap, Vinit Singh, Muhammad Tayyeb, Ali Jaan, Gaurav Mohan, Trishala Meghal
Journal: Journal of Clinical Oncology (2022)

e13068 Background: Sacituzumab govitecan (SG) is an drug-antibody conjugate composed of anti-trophoblast cell-surface antigen 2 (Trop-2) IgG1 Kappa antibody with SN-38 through a hydrolysable linker. SG has a promising efficacy safety profile in triple negative breast cancer (TNBC) and was given regular approval for nonresectable locally advanced or metastatic disease with 2 or more previous line of therapies. This review aims to explore the efficacy and safety of SG-regimens for the treatment of TNBC. Methods: We conducted a literature search using three databases (PubMed, Embase, and ClinicalTrials.gov). Our search strategy included MeSH and keywords for breast cancer and SG including trade and generic names from the date of inception to January 15, 2022. Initial databases yielded 275 articles. After exclusion, two clinical trials on the use of SG in pretreated TNBC were included. Results: Among a total of 963 enrolled patients, 379 patients were evaluated. Majority of the patients received SG dose of 10 mg/kg. Bardia et al. studied the efficacy of SG in TNBC pts (n = 235) in phase III (ASCENT) trial achieved an overall response rate (ORR) of 31%. The median overall survival (OS) was 11.8 months (95% CI 10.5-13.8) and a median progression-free survival (PFS) was 4.8 months (95% CI, 4.1-5.8).Similarly, in another study Bardia et al. studied SG in TNBC pts (n = 144) in phase I/II (basket) trial and observed ORR of 33.3%. The median overall survival (OS) was 13 months (95% CI, 11.2 to 14) and a median progression-free survival (PFS) was 5.6 months (95% CI, 4.8 to 6.6). (Table) Diarrhea and Nausea was the most common adverse effect reported by the patient whereas neutropenia was the most common grade 3 adverse effect. Conclusions: SC showed promising outcomes in terms of ORR for the treatment of TNBC. [Table: see text] [Table: see text]
Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?
Authors: Heather Hampel, Matthew B. Yurgelun
Journal: Journal of Clinical Oncology (2022)

Use of germline genetic testing among patients with cancer is increasing because of (1) the availability of multigene panel tests that include multiple cancer susceptibility genes in a single test, (2) decreased costs of these tests and improvements in insurance coverage, and (3) US Food and Drug Administration-approval of genotype-directed therapies such as poly(ADP-ribose) polymerase inhibitors for individuals with certain cancers and pathogenic germline variants in BRCA1 and BRCA2 (with possible benefits with other genes in the homologous repair deficiency pathway). In addition, National Comprehensive Cancer Network guidelines have already endorsed germline genetic testing for all patients with certain cancer types (epithelial ovarian cancer, exocrine pancreatic cancer, and high-grade/metastatic prostate cancer), regardless of age or personal/family history of cancer. Herein, we debate the pros and cons of offering germline multigene panel testing to all patients diagnosed with any GI cancer. The authors agree that it may just be a matter of time before germline multigene panel testing is offered to all patients with cancer; however, this article will highlight some of the benefits, risks, and limitations of this approach so that research can help fill some of the gaps to ensure that genetic medicine continues to be implemented in ways that improve real-world patient care and outcomes.
International Classification of Diseases codes do not capture all cases of hidradenitis suppurativa in the electronic health record: a retrospective cohort
Authors: Pauleatha Diggs Bonds, Joyce Huang, Jacqueline Ike, Eric Mukherjee, Lynn Petukhova, Lee Wheless
Journal: British Journal of Dermatology (2022)

Journal Article International Classification of Diseases codes do not capture all cases of hidradenitis suppurativa in the electronic health record: a retrospective cohort Get access Pauleatha Diggs Bonds, Pauleatha Diggs Bonds Department of Dermatology Vanderbilt University Medical Center Nashville TN USA https://orcid.org/0000-0002-0779-016X Search for other works by this author on: Oxford Academic Google Scholar Joyce Huang, Joyce Huang Department of Dermatology Vanderbilt University Medical Center Nashville TN USADepartment of Surgery, Division of Plastic Surgery University of Texas Medical Branch Galveston TX USA Search for other works by this author on: Oxford Academic Google Scholar Jacqueline Ike, Jacqueline Ike Meharry Medical College Nashville TN USA Search for other works by this author on: Oxford Academic Google Scholar Eric Mukherjee, Eric Mukherjee Department of Dermatology Vanderbilt University Medical Center Nashville TN USA Search for other works by this author on: Oxford Academic Google Scholar Lynn Petukhova, Lynn Petukhova Departments of Dermatology and Epidemiology Columbia University Medical Center New York NY USA https://orcid.org/0000-0002-1573-1653 Search for other works by this author on: Oxford Academic Google Scholar Lee Wheless Lee Wheless Department of Dermatology Vanderbilt University Medical Center Nashville TN USA Correspondence: Lee Wheless. Email: lee.e.wheless@vumc.org https://orcid.org/0000-0002-8162-5971 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 187, Issue 5, 1 November 2022, Pages 787–788, https://doi.org/10.1111/bjd.21695 Published: 01 November 2022
Overall survival (OS) with first-line atezolizumab (A) or placebo (P) in combination with vemurafenib (V) and cobimetinib (C) in <i>BRAF</i><sup>V600</sup> mutation-positive advanced melanoma: Second interim OS analysis of the phase 3 IMspire150 study.
Authors: Grant A. McArthur, Ralf Gutzmer, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Svetlana Protsenko, Rodrigo Perez Pereira, Thomas Eigentler, Piotr Rutkowski, Lev V. Demidov, Natalia V. Zhukova, Jacob Schachter, Yibing Yan, Ivor Caro, Christian Hertig, Cloris Xue, Lieke Kusters, Paolo Antonio Ascierto, Karl D. Lewis
Journal: Journal of Clinical Oncology (2022)

9547 Background: Primary analysis of the phase 3 IMspire150 study (NCT02908672) demonstrated improved investigator-assessed progression-free survival (PFS) with first-line A + V + C vs P + V + C in patients (pts) with BRAF V600 mutation–positive advanced melanoma (hazard ratio [HR] 0.78; 95% CI, 0.63-0.97; P= 0.025). With median follow-up of 18.9 months at primary analysis, OS data were immature; interim analysis of OS at the time of the primary analysis demonstrated a trend in favor of A + V + C over P + V + C (estimated 2-year OS rate, 60.4% vs 53.1%) (Gutzmer et al. Lancet 2020;395:1835-1844). Herein, we present results from the second interim OS analysis of the IMspire150 study. Methods: IMspire150 enrolled previously untreated pts with stage IV or unresectable stage IIIc BRAF V600 mutation-positive melanoma (n = 514). Pts were randomized 1:1 to receive 28-day cycles of A + V + C (n = 256) or P + V + C (n = 258). Pts received V + C in cycle 1; A or P was added on days 1 and 15 from cycle 2 onwards. The second interim OS analysis was planned after ̃270 OS events were recorded, and was projected to have a minimally detectable difference of HR of 0.74 with a P value boundary of 0.0140. OS was estimated using the Kaplan-Meier method. Results: At data cutoff (Sept 8, 2021), 273 OS events had occurred. Median follow-up was 29.1 months (range, 1-54) for A + V + C and 22.8 months (range, 0-54) for P + V + C. A continued trend toward OS benefit in favor of A + V + C over P + V + C was observed with median OS of 39.0 vs 25.8 months, but the difference did not reach statistical significance (HR, 0.84; 95% CI, 0.66-1.06; P= 0.1432). A delayed treatment effect was observed, with landmark OS rates for A + V + C vs P + V + C of 76.1% vs 76.5% at 12 months and 61.5% vs 53.3% at 24 months. With additional follow-up, A + V + C continued to show PFS benefit over P + V + C (HR, 0.79; 95% CI, 0.64-0.97; P= 0.0224); overall response rates (66.7% vs 65.0%) and median duration of response (21.0 vs 12.6 months) remained consistent with those reported at primary analysis. No new safety signals were observed with additional follow-up. Conclusions: With further follow-up, A + V + C demonstrated a consistent, but not statistically significant, improvement in OS and continued benefit in duration of response versus P + V + C in previously untreated pts with BRAF V600 mutation–positive advanced melanoma. Clinical trial information: NCT02908672.